N-[4-O-hydroxyphenyl-1,3-dioxan-5-ylhexenoyl]sulphonamides

ABSTRACT

The invention concerns novel N-[4(Z)-6-(4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl)hexanoyl]sulphonamide derivatives of formula I of value as therapeutic agents. 
     R 1  is typically an alkoxyalkyl or phenoxyalkyl radical as defined hereinafter and R 2  is alkyl, benzyl or phenyl. The invention also discloses salts of the formula I compounds as well as pharmaceutical compositions containing the compounds and processes for the production of the compounds.

This invention concerns novel amide derivatives and, more particularlynovelN-[4(Z)-6-(4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl)hexenoyl]sulphonamidederivatives which antagonise one or more of the actions of thromboxaneA₂ (hereafter referred to as "TXA₂ ") and which are of value astherapeutic agents. The invention also concerns novel pharmaceuticalcompositions containing one of the novel derivatives and processes andintermediates for use in the manufacture of the novel amide derivatives.

It is known that TXA₂ is a potent aggregator of blood platelets and apowerful vasoconstrictor. TXA₂ is also a potent constrictor of bronchialand tracheal smooth muscle. TXA₂ may therefore be involved in a widevariety of disease conditions, for example ischaemic heart disease suchas myocardial infarction, angina, cerebrovascular disease such astransient cerebral ischaemia, migraine and stroke, peripheral vasculardisease such as atherosclerosis, microangiopathy, hypertension and bloodclotting defects due to lipid imbalance, and pulmonary disease such aspulmonary embolism, bronchial asthma, bronchitis, pneumonia, dyspnoeaand emphysema. Accordingly, compounds which antagonise the actions ofTXA₂ may be expected to have therapeutic value in the prevention ortreatment of any one or more of the above mentioned diseases or anyother disease conditions in which it is desirable to antagonise theactions of TXA₂.

In our European patent application, publication number 94239, there isdescribed a series of 4-phenyl-1,3-dioxan-5-ylalkenoic acid derivativesof the formula Z having cis relative stereochemistry at positions 4 and5 of the dioxane ring and wherein Ra and Rb are variously hydrogen,alkyl, halogenoalkyl, alkenyl and optionally substituted aryl orarylalkyl, Rc is hydroxy, alkoxy or alkanesulphonamido, n is 1 or 2, Ais ethylene or vinylene, Y is (2-5C)polymethylene optionally substitutedby alkyl and benzene ring B bears one or two optional substituents. Wehave now discovered (and herein lies the basis of our invention). thatparticularly useful TXA₂ antagonism is also shown by a novel group ofamide derivatives of formula Z in which benzene ring B iso-hydroxyphenyl, n is 1, A is cis-vinylene, Y is ethylene and Rc issulphonamido, as defined below.

According to the invention there is provided aN-[4(Z)-6-(4-o-hydroxyphenyl-1,3-dioxan-5-yl)hexenoyl]sulphonamide ofthe formula I set out hereinafter wherein R¹ is a group of the formulaR³ O.CR⁴ R⁵ -- in which R³ is (1-6C)alkyl or phenyl, the latteroptionally bearing a substituent selected from halogeno, cyano, nitro,trifluoromethyl and (1-4C)alkoxy, and R⁴ and R⁵ are independently(1-4C)alkyl; and R² is (1-6C)alkyl, benzyl or phenyl, the latter two ofwhich may optionally bear a halogeno, (1-4C)alkyl, (1-4C)alkoxy,trifluoromethyl, cyano or nitro substituent; and the substituents atpositions 4 and 5 of the dioxane ring in formula I and the substituentR¹ have cis-relative stereochemistry; or a pharmaceutically acceptablesalt therof.

It will be appreciated that the compounds of formula I possessasymmetric carbon atoms and may exist and be isolated in racemic andoptically active forms. The invention includes both the racemic formsand any optically active form (or mixtures thereof) which is capable ofantagonising one or more of the actions of TXA₂, it being well known inthe art how to prepare individual optical isomers (for example bysynthesis from optically active starting materials or resolution of aracemic form) and how to determine the TXA₂ antagonist properties usingone or more of the standard tests referred to hereafter.

In the chemical formulae attached hereto, although a particularconfiguration is shown, this does not necessarily correspond to theabsolute configuration.

A particular value for R⁴ or R⁵ is, for example, methyl or ethyl, andpreferably methyl. It is generally preferred that R⁴ and R⁵ totaltogether no more than 4 carbon atoms.

A particular value for an optional substituent which may be present onR² or R³ when it is phenyl or on R² when it is benzyl, as defined above,is, for example: fluoro, chloro or bromo, for halogeno; methyl or ethyl,for (1-4C)alkyl; and methoxy or ethoxy, for (1-4C)alkoxy.

Particular pharmaceutically acceptable salts of the sulphonamidederivatives of formula I are, for example: alkali metal and alkalineearth metal salts, such as lithium, sodium, potassium, magnesium andcalcium salts; aluminium and ammonium salts; and salts with organicamines and quaternary bases forming physiologically acceptable cations,such as salts with methylamine, dimethylamine, trimethylamine,ethylenediamine, piperidine, morpholine, pyrrolidine, piperazine,ethanolamine, triethanolamine, N-methylglucamine, tetramethylammoniumhydroxide and benzyltrimethylammonium hydroxide.

Specific values for R¹ which are of special interest include forexample, 1-[(1-4C)alkoxy]-1-methylethyl, and 1-methyl-1-phenoxyethyl(optionally bearing a fluoro, chloro, bromo, cyano or nitro substituenton the phenoxy moiety) and for R² include, for example, methyl, ethyland phenyl optionally bearing a fluoro, chloro, bromo, cyano, nitro,trifluoromethyl or methoxy substituent.

A specific value for R² when it is (1-6C)alkyl is for example, methyl,ethyl, propyl or isopropyl.

A preferred value for R¹ is 1-methoxy-1-methylethyl or1-methyl-1-phenoxyethyl, and for R² is methyl or ethyl.

A particular value for R³ when it is (1-6C)alkyl is, for example,methyl, ethyl or propyl.

A specific compound of formula I of particular interest is set out inthe accompanying Example 1. This compound, or a pharmaceuticallyacceptable salt thereof is provided as a separate feature of theinvention.

The compounds of formula I may be manufactured by conventionalprocedures of organic chemistry well known in the art for themanufacture of structurally analogous compounds. Such procedures areprovided as a further aspect of the invention and are illustrated by thefollowing processes in which R¹, R², R³, R⁴ and R⁵, have any of themeanings herein above:

(a) An aldehyde of the formula II is reacted with a Wittig reagent ofthe formula

R'₃ P═CH.(CH₂)₂.CO.N⁻.SO₂ R² M⁺ wherein R' is (1-6C)alkyl or aryl(especially phenyl) and M⁺ is a cation, for example an alkali metalcation, such as the lithium, sodium or potassium cation. The process ingeneral produces compounds of formula I in which the substituentsadjacent to the double bond have predominantly cis-relativestereochemistry i.e. the `Z` isomer.

The process is conveniently performed in a suitable solvent or diluent,for example an aromatic solvent such as benzene, toluene orchlorobenzene, an ether such as 1,2-dimethoxyethane, t-butyl methylether, dibutyl ether or tetrahydrofuran, in dimethyl sulphoxide ortetramethylene sulphone, or in a mixture of one or more such solvents ordiluents. The process is generally performed at a temperature in therange, for example, -80° C. to 40° C., but is conveniently performed ator near room temperature, that is in the range 0° to 35° C.

(b) A phenol derivative of the formula III, wherein R" is a suitableprotecting group, for example (1-6C)alkyl (such as methyl or ethyl),acyl (such as acetyl, benzoyl, methanesulphonyl or p-toluenesulphonyl),allyl, tetrahydropyran-2-yl or trimethylsilyl, is deprotected.

The precise deprotection conditions used depend on the nature of theprotecting group R". Thus, for example, when it is methyl or ethyl thedeprotection may be carried out by heating with sodium thioethoxide in asuitable solvent (such as N,N-dimethylformamide or1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone) at a temperature inthe range, for example, 60°-160° C. When the protecting group is acyl itmay be removed, for example, by hydrolysis in the presence of a base(such as sodium or potassium hydroxide) in a suitable aqueous solvent[such as an aqueous (1-4C)alkanol] at a temperature in the range, forexample, 0°-60° C. When the protecting group is allyl ortetrahydropyran-2-yl it may be removed, for example, by treatment withstrong acid such as trifluoroacetic acid and when it is trimethylsilyl,it may be removed, for example, by reaction with aqueoustetrabutylammonium fluoride or sodium fluoride, using a conventionalprocedure.

(c) An erythro-diol derivative of the formula IV, wherein one of Q¹ andQ² is hydrogen and the other is hydrogen or a group of the formula--CRaRb.OH (wherein Ra and Rb are the same or different (1-4C)alkyl), isreacted with an aldehyde of the formula R¹.CO.H, or with an acetalhemiacetal or hydrate thereof.

The aldehyde [or its hydrate, or its acetal or hemiacetal with a(1-4C)alkanol (such as methanol or ethanol)] is generally used inexcess.

The reaction is generally performed in the presence of an acid catalyst,such as hydrogen chloride, hydrogen bromide, sulphuric acid, phosphoricacid, methanesulphonic acid, p-toluenesulphonic acid, or an acidicresin, conveniently in the presence of a suitable solvent or diluent,such as toluene, xylene or an ether, for example tetrahydrofuran,dibutyl ether, methyl t-butyl ether or 1,2-dimethoxyethane, and attemperature in the range, for example 0° to 80° C.

Those starting materials of formula IV wherein Q¹ and Q² are bothhydrogen may be obtained, for example, by mild acid catalysed hydrolysisor alcoholysis of the dioxane ring of a compound of formula V wherein Raand Rb are both alkyl, such as methyl or ethyl. The hydrolysis oralcoholysis will normally be carried out a temperature in the range 10°to 80° C. using an aqueous mineral acid such as hydrochloric acid, in analkanol (such as ethanol or 2-propanol) or an ether (such astetrahydrofuran), as solvent.

Those starting materials of formula IV wherein one of Q¹ and Q² ishydrogen and the other is a group of the formula --CRaRb.OH areintermediates in the above-mentioned formation of the starting materialsof formula IV wherein Q¹ and Q² are both hydrogen. However, saidintermediates are not normally isolated or characterised. Accordingly,the invention also provides a modification of process (c) whichcomprises reacting a compound of formula V wherein one of Ra and Rb ishydrogen, methyl or ethyl and the other is methyl or ethyl, with anexcess of an aldehyde of the formula R¹.CO.H or an acetal, hemiacetal orhydrate thereof, in the presence of an acid-catalyst(such as one ofthose given above), conveniently at a temperature in the range, forexample, 10° to 80° C. and optionally in the presence of a suitablesolvent or diluent (such as one of those given above).

The starting materials for use in the above processes may be made bygeneral procedures of organic chemistry, known for the preparation ofstructurally related compounds, for example by analogy with thoseprocedures disclosed in European patent application, publication No.94239.

The protected phenol derivatives of formula III may be made, forexample, by using an analogous procedure to process (a) above, using analdehyde analogous to formula II but wherein the phenol group has beenprotected with the group R". The starting materials of formula V may beobtained, for example, using analogous procedures to those described inEuropean patent application, publication No. 94239.

The necessary Wittig reagents may be obtained, for example, byconventional procedures, for example by treating the correspondingphosphonium halides with a strong base, such as sodium hydride, lithiumdiisopropylamide, potassium t-butoxide or butyllithium. They aregenerally formed in situ just prior to carrying out the condensationprocess (a) above.

The necessary starting materials of formula III may conveniently be,obtained for example, by reacting the corresponding protected acid offormula VI with a sulphonamide of the formula H₂ N.SO₂ R² and a suitabledehydrating agent, for example N,N'-dicyclohexylcarbodiimide, optionallytogether with an organic base, for example 4-(dimethylamino)pyridine, inthe presence of a suitable solvent or diluent, for example methylenechloride at a temperature in the range, 10°-50° C., but preferably at ornear room temperature. Alternatively, a reactive derivative of the acidof formula VI, for example an acid halide (such as the acid chloride),may be reacted with an alkali metal salt (such as the sodium salt) ofthe appropriate sulphonamide, conveniently at or near room temperatureand in a suitable solvent or diluent, for example an ether,N,N-dimethylformamide or methylene chloride.

When a salt of a compound of formula I is required, it may be obtainedby reaction with the appropriate base affording a physiologicallyacceptable cation, or by any other conventional procedure.

Further, when an optionally active form of a compound of formula I isrequired, one of the aforesaid processes is carried out using anoptically active starting material. Alternatively, the racemic form of acompound of formula I may be reacted with an optically active form of asuitable organic base, for example ephedrine,N,N,N-trimethyl(1-phenylethyl)ammonium hydroxide or 1-phenylethylamine,followed by conventional separation of the diastereoisomeric mixture ofsalts thus obtained, for example by fractional crystallisation from asuitable solvent, for example a (1-4C)alkanol, whereafter the opticallyactive form of said compound of formula I may be liberated by treatmentwith acid using a conventional procedure for example using an aqueousmineral acid such as dilute hydrochloric acid.

Many of the intermediates defined herein are novel, for example thephenol derivatives of formula III, and are provided as further separatefeatures of the invention.

As stated earlier, the compounds of formula I are antagonists of one ormore of the actions of TXA₂, for example certain of its actions on bloodplatelets, the vasculature and/or the lung. The antagonism may bedemonstrated in one or other of the following standard tests:

(a) The rabbit aortal strip model devised by Piper and Vane (Nature,1969, 223, 29-35) or the rat aortal strip model developed by Kennedy etalia (Prostaglandins, 1982, 24, 667-689) using as agonist the TXA₂mimetic agent known as U46619 (described by R L Jones et alia in"Chemistry, Biochemistry and Pharmacological Activity of Prostanoids"edited by S M Roberts and F Scheinmann, at page 211; Pergamon Press,1979) may be used as the agonist; and

(b) a blood platelet aggregation test based on that described by Born(Nature, 1962, 194, 927-929) and involving:

(i) aggregating human, citrated, platelet-rich plasma by addition of theTXA₂ mimetic agent U46619 so that a dose-response curve is generated;

(ii) generating a dose-response curve for U46619 stimulated plateletaggregation in the presence of increasing amounts of test compound(generally in the range 10⁻⁵ M to 10⁻¹⁰ M); and

(iii) calculating a K_(B) value indicating potency of TXA₂ antagonismfor the test compound, averaged over several concentrations, from thecalculated 50% response value for U46619 aggregation in the presence andabsence of test compound; and

(c) a bronchoconstriction test involving measuring the inhibition by atest compound of the bronchoconstriction induced in the Konzett-Rossler,anaesthetised guinea-pig model (as modified by Collier and James,Brit.J.Pharmacol., 1967, 30, 283-307) by intravenous administration ofthe TXA₂ mimetic agent, U46619 and involving:

(i) obtaining a cumulative dose-response curve to U46619 inducedbronchoconstriction by intravenous administration of constant volumes ofincreasing concentrations of U46619 (0.2-4 μg/kg) in physiologicalsaline solution and expressing bronchoconstriction as the maximum ofthat theoretically obtainable with no air flow to the test animal;

(ii) generating a cumulative dose-response curve to U46619 inducedbronchoconstriction at 30 minute intervals for 3 hours after oral dosingof test compound; and

(iii) calculating a dose-ratio for the test compound (that is the ratioof concentration of U46619 required to cause 50% bronchoconstriction inthe presence and absence of test compound) indicating the potency ofTXA₂ antagonism.

The antagonism of the effects of TXA₂ on the vasculature may bedemonstrated, for example in rats in the following manner:

(d) Male rats (Alderley Park strain) are anaesthetised with sodiumpentobarbital and blood pressure is monitored at the carotid artery. TheTXA₂ mimetic agent U46619 is administered intravenously at 5 μg/kg viathe jugular vein to produce 20-30 mm/Hg (2640-3970 pascal) increase insystolic blood pressure. The process is repeated twice to ensureadequacy of response. A test compound is then administered eitherintravenously (via the jugular vein) or orally (via a cannula) directlyinto the stomach and the animal challenged with U46619, five minutesafter dosing with test compound and then successively every ten minutesuntil the hypertensive effect of U46619 is no longer blocked.

Further, the antagonism of the effects of TXA₂ in vivo may bedemonstrated, for example, by assessing the effects of a test compoundon the aggregation of blood platelets obtained after administration oftest compound to a test animal, such as a rabbit, rat, guinea pig ordog, using standard procedures similar to that described in (a) above.However, when the aggregation of dog platelets is being studied it isnecessary to use a predetermined, threshold concentration of theplatelet aggregation agent adenosine diphosphate (about 0.4-1.2×10⁻⁶ M)together with the TXA₂ mimetic agent, U46619.

By way of illustration, the compound described in the accompanyingExample 1 hereafter possesses a K_(B) of 5.4×10⁻⁹ M in procedure (b)above.

In general, other compounds of formula I show the following levels ofTXA₂ antagonist properties in one or more of the above mentioned testse.g. test (a) pA₂ >6.0; test (b) K_(B) : <1.0×10⁻⁶ M; test (c) doseratio>5, 2 hours after oral dosing at 10 mg/kg or less and/or test (d),significant inhibition of U46619 induced hypertension for at least 1hour following oral dosing at 25 mg/kg or less, without any overttoxicity in tests (c) or (d).

As stated previously, the compounds of formula I may be used in thetherapy or prevention of diseases or adverse conditions in warm-bloodedanimals in which it is desirable to antagonise one or more of theactions of TXA₂. In general, a compound of formula I will beadministered for this purpose by an oral, rectal, intravenous,subcutaneous, intramuscular or inhalation route, so that a dose in therange, for example 0.01-5 mg/kg body weight, will be given up to fourtimes per day, varying with the route of administration, the severity ofthe condition and the size and age of the patient under treatment.

The compounds of formula I will generally be used in the form of apharmaceutical composition comprising a compound of formula I, or apharmaceutically acceptable salt thereof, as defined hereinabove,together with a pharmaceutically acceptable diluent or carrier. Such acomposition is provided as a further feature of the invention and may bein a variety of dosage forms. For example, it may be in the form oftablets, capsules, solutions or suspensions for oral administration; inthe form of a suppository for rectal administration; in the form of asterile solution or suspension for administration by intravenous orintramuscular injection; in the form of an aerosol or a nebulisersolution or suspension, for administration by inhalation; and in theform of a powder, together with pharmaceutically acceptable inert soliddiluents such as lactose, for administration by insufflation.

The pharmaceutical compositions may be obtain by conventional proceduresusing pharmaceutically acceptable diluents and carriers well known inthe art. Tablets and capsules for oral administration may convenientlybe formed with an enteric coating, for example comprising celluloseacetate phthalate, to minimise contact of the active ingredient offormula I with stomach acids.

The pharmaceutical compositions of the invention may also contain one ormore agents known to be of value in diseases or conditions intended tobe treated; for example a known platelet aggregation inhibitor,hypolipidemic agent, anti-hypertensive agent, beta-adrenergic blocker ora vasodilator may usefully also be present in a pharmaceuticalcomposition of the invention for use in treating a heart or vasculardisease or condition. Similarly, by way of example, an anti-histamine,steroid (such as beclomethasone dipropionate), sodium cromoglycate,phosphodiesterase inhibitor or a beta-adrenergic stimulant may usefullyalso be present in a pharmaceutical composition of the invention for usein treating a pulmonary disease or condition. A composition according tothe invention may also advantageously contain an inhibitor ofthromboxane A₂ synthetase, for example dazoxiben or furegrelate(U.63557).

In addition to their use in therapeutic medicine, the compounds offormula I are also useful as pharmacological tools in the developmentand standardisation of test systems for the evaluation of the effects ofTXA₂ in laboratory animals such as cats, dogs, rabbits, monkeys, ratsand mice, as part of the search for new therapeutic agents. Thecompounds of formula I may also be used because of their TXA₂ antagonistproperties in helping to maintain the viability of blood and bloodvessels in warm-blooded animals (or parts thereof) under-goingartificial extracorporeal circulation, for example during limb or organtransplants. When used for this purpose a compound of the formula I, ora physiologically acceptable salt thereof, will generally beadministered so that a steady state concentration in the range, forexample, 0.1 to 10 mg. per liter is achieved in the blood.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo;

(ii) operations were carried out at room temperature, that is in therange 18°-26° C. and under an atmosphere of an inert gas such as argon;

(iii) flash column and medium pressure liquid chromatography (MPLC)chromatography were performed on Merck Kieselgel (Art. 9385) obtainedfrom E. Merck, Darmstadt, W. Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) proton NMR spectra were normally determined at 90 or 200 MHz inCDCl₃ using tetramethylsilane (TMS) as an internal standard, and areexpressed as chemical shifts (delta values) in parts per millionrelative to TMS using conventional abbreviations for designation ofmajor peaks: s, singlet; m, multiplet; t, triplet; br, broad; d,doublet;

(vi) all end-products were isolated as racemates.

EXAMPLE 1

Ethanethiol (0.75 ml) was added over 15 minutes to a stirred suspensionof sodium hydride (485 mg, 50% w/w dispersion in oil) in1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (25 ml) at 4°C., maintained under an argon atmosphere. After 10 minutes thetemperature was raised to 80° C. and a solution ofN-methanesulphonyl-4(Z)-6-([2,4,5-cis]-2-[1-methyl-1-phenoxyethyl]-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenamide(A) (871 mg) in DMPU (5 ml) was added. The mixture was stirred for 3.5hours at 80° C. and for a further 1 hour at 100° C., then cooled to 10°C. and poured into an ice-water mixture (100 ml). The aqueous mixturewas washed with dichloromethane (2×50 ml). The aqueous phase wasacidified to pH3 with 2M hydrochloric acid and extracted with ether(3×50 ml). These extracts were washed with water (2×50 ml) and saturatedbrine (50 ml), then dried (MgSO₄) and evaporated. The oil obtained waspurified by flash chromatography, using hexane/ethyl acetate/acetic acid(60:40:1 v/v) as eluant, to giveN-methanesulphonyl-4(Z)-6-([2,4,5-cis]-2-[1-methyl-1-phenoxyethyl]-4-o-hydroxyphenyl-1,3-dioxan-5-yl)hexenamideas a colourless oil (456 mg); NMR: 1.37 (6H, s), 1.88 (2H, m), 2.33 (4H,m), 2.67 (1H, m), 3.22 (3H, s), 4.00 (1H, dm J=11 Hz), 4.22 (1H, ddJ=11,1 Hz), 4.78 (1H, s), 5.32 (1H, d J=2 Hz), 5.40 (2H, m), 7.08 (9H,m); m/e 521 (M+NH₄)⁺.

The starting material (A) was obtained as follows:

(i) A solution of(4-o-methoxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl)acetaldehyde,(European patent application, publication No. 94239A, p41) (15.8 g) indry THF (75 ml) was added under argon to a stirred, ice-cooled solutionof the ylid prepared from (3-carboxypropyl)triphenylphosphonium bromide(51.48 g) and potassium t-butoxide (26.88 g) in dry THF (400 ml). Themixture was stirred for 15 minutes at 4° C., then for 1.5 hours atambient temperature and was then poured into ice-water (1 liter). Themixture obtained was washed with 50% v/v ether/hexane (2×250 ml) toremove the bulk of neutral material. The aqueous phase was acidified topH 5 with acetic acid and extracted with ether (4×300 ml). Theseextracts were washed successively with water (3×150 ml), and saturatedbrine (2×100 ml), then dried (MgSO₄) and evaporated. The residue waspurified by flash chromatography, eluting with toluene/ethylacetate/acetic acid (80:20:2 v/v). The solid obtained was crystallisedfrom 10% v/v ethyl acetate/hexane (250 ml) to give4(Z)-6-(4-o-methoxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl)hexenoic acid(B) (13.0 g), m.p. 99°-101° C.; NMR: 1.52 (3H, s), 1.54 (1H, m), 1.56(3H, s), 1.80 (1H, m), 2.28 (4H, m), 2.49 (1H, m), 3.77 (1H, dd J=11,1Hz), 3.82 (3H, s), 4.16 (1H, dm J=11 Hz), 5.28 (2H, m), 5.45 (1H, d J=2Hz), 6.82 (1H, dd J=7, 1 Hz), 6.97 (1H, td J=7, 1 Hz), 7.22 (1H, td J=8,1 Hz), 7.48 (1H, dm J=8 Hz).

(ii) A suspension of the hexenoic acid (B) (1.5 g) in2-methyl-2-phenoxypropionaldehyde (3.0 g) containing p-toluenesulphonicacid (10 mg) was stirred for 18 hours at ambient temperature and thenheated at 60° C. for 6 hours. The cooled solution was diluted with ether(30 ml) and extracted with 0.5M sodium hydroxide solution (3×10 ml). Theaqueous extracts were washed with ether (20 ml), then acidified to pH5with acetic acid and extracted with ether (3×15 ml). These extracts werewashed successively with water (2×10 ml) and saturated brine (10 ml),then dried (MgSO₄) and evaporated. The residue was purified by MPLC,eluting with hexane/ethyl acetate/acetic acid (85:15:1 v/v), to give4(Z)-6-([2,4,5-cis]-2[1-methyl-1-phenoxyethyl]-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenoicacid (C) as a clear oil (655 mg); NMR: 1.34 (3H, s) 1.42 (3H, s), 1.57(1H, m), 1.89 (1H, m), 2.30 (4H, m), 2.49 (1H, m), 3.81 (3H, s), 3.98(1H, dm J=11 Hz), 4.15 (1H, dd J=11, 1 Hz), 4.80 (1H, s), 5.24 (1H, dJ=2 Hz), 5.32 (1H, m), 6.85 (1H, ddJ=7, 1 Hz), 7.03 (4H, m), 7.24 (3H,m), 7.43 (1H, dd J=7, 1.5 Hz); m/e 458 (M⁺ +NH₄), 441 (M⁺ +H).

[The necessary 2-methyl-2-phenoxypropionaldehyde was itself obtained asfollows:

A stirred solution of methyl 2-methyl-2-phenoxypropionate (3.88 g) indichloromethane (100 ml) was treated dropwise at -70° C. under argon,with a 1M solution of diisobutylaluminium hydride (dibal) indichloromethane (21 ml). The solution was stirred for 1 hour at -70° C.,then allowed to warm to -30° C., after which it was poured into avigorously stirred aqueous solution of potassium sodium tartratetetrahydrate (50 g) dissolved in water (100 ml) cooled to 4° C. Afterstirring for 30 minutes, the mixture was separated by filtration throughdiatomaceous earth. The filtrate was extracted with ether (4×100 ml) andthe extracts were washed with saturated brine (2×100 ml), dried (MgSO₄)and evaporated. The residual oil (3.18 g) containing2-methyl-2-phenoxypropionaldehyde was used without furtherpurification.]

(iii) Dicyclohexylcarbodiimide (1.08 g) was added to a solution of theoil C (2.13 g), 4-(dimethylamino)pyridine (0.61 g) andmethanesulphonamide (0.48 g) in dichloromethane (20 ml). The mixture wasstirred for 1 hour at 4° C. then for 18 hours at ambient temperature.The precipitated N,N'-dicyclohexylurea was removed by filtration byfiltration, and washed with dichloromethane. The filtrate and washingswere extracted with 0.1M sodium hydroxide (65 ml). The basic extract wasacidified with acetic acid and extracted with ether (3×50 ml). Theseextracts were washed with water (2×50 ml) and saturated brine (50 ml),then dried (MgSO₄) and evaporated. The oil obtained was purified byMPLC, eluting with hexane/ethyl acetate/acetic acid (75:25:1 v/v), togiveN-methanesulphonyl-4(Z)-6-([2,4,5-cis]-2-[1-methyl-1-phenoxyethyl]-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenamide(A) as a clear oil (1.77 g); NMR: 1.35 (3H, s), 1.42 (3H, s), 1.52 (1H,m), 1.94 (1H, m), 2.36 (4H, m), 2.54 (1H, m), 3.21 (3H, s), 3.83 (3H,s), 4.00 (1H, dm J=11 Hz), 4.18 1H, dd J=11, 1 Hz), 4.79 (1H, s), 5.27(1H, d J=2 Hz), 5.37 (2H, m), 6.88 (1H, bd J=7 Hz), 6.99 (1 H, td J=7, 1Hz), 7.09 (3H, m), 7.27 (3H, m), 7.42 (1H, m); m/e 535 (M+NH₄)⁺.

EXAMPLE 2

An illustrative dosage form of a composition of the invention isprovided by the following capsule formulation:

    ______________________________________                                                       mg/capsule                                                     ______________________________________                                        Compound X       10                                                           Lactose Ph. Eur  588.5                                                        Magnesium stearate                                                                             1.5                                                          ______________________________________                                    

The capsules may conveniently be of hard gelatine and are filled inconventional manner. Compound X is a compound of formula I or a saltthereof as defined hereinbefore, for example the compound of Example 1or a salt thereof. ##STR1##

What is claimed is:
 1. A sulphonamide derivative of the formula I set out belowwherein R¹ is a group of the formula R³ O.CR⁴ R⁵ -- in which R³ is (1-6C)alkyl or phenyl, the latter optionally bearing a substituent selected from halogeno, cyano, nitro, trifluoromethyl and (1-4C)alkoxy, and R⁴ and R⁵ are independently (1-4C)alkyl; and R² is (1-6C)alkyl, benzyl or phenyl, the latter two of which may optionally bear a halogeno, (1-4C)alkyl, (1-4C)alkoxy, trifluoromethyl, cyano or nitro substituent; and the substituents at positions 4 and 5 of the dioxane ring in formula I and the substituent R¹ have cis-relative stereochemistry; or a pharmaceutically acceptable salt thereof.
 2. A compound as claimed in claim 1 wherein R³ is methyl, ethyl, propyl, isopropyl or phenyl, the latter optionally bearing a substituent selected from fluoro, chloro, bromo, cyano, nitro, trifluoromethyl, methoxy and ethoxy; R⁴ and R⁵ are independently methyl or ethyl; and R² is methyl, ethyl, propyl, benzyl or phenyl, the latter two optionally bearing a fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, cyano or nitro substituent.
 3. A compound as claimed in claim 1 wherein R¹ is 1-[(1-4C)alkoxy]-1-methylethyl or 1-methyl-1-phenoxyethyl, the latter optionally bearing a fluoro, chloro, bromo, cyano or nitro substituent on the phenoxy moiety, and R² is methyl, ethyl or phenyl, the latter optionally bearing a fluoro, chloro, bromo, cyano, nitro, trifluoromethyl or methoxy substituent.
 4. A compound as claimed in claim 1 wherein R¹ is 1-methoxy-1-methylethyl or 1-methyl-1-phenoxyethyl.
 5. A compound as claimed in claim 4 wherein R² is methyl or ethyl.
 6. N-Methanesulphonyl-4(Z)-6-([2,4,5-cis]-2-[1-methyl-1-phenoxyethyl]-4-o-hydroxyphenyl-1,3-dioxan-5-yl)hexenamide, or a pharmaceutically acceptable salt thereof.
 7. A salt as claimed in any one of claims 1-6 which is selected from alkali metal, alkaline earth metal, aluminium and ammonium salts, and from salts with organic amines and quaternary bases forming physiologically acceptable cations.
 8. A pharmaceutical composition for antagonizing one or more of the actions of thromboxane A₂ which comprises a thromboxane A₂ antagonistically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, together with a pharmaceutically acceptable diluent or carrier.
 9. A composition as claimed in claim 8 which comprises as an additional active ingredient, an inhibitor of thromboxane A₂ synthesis.
 10. A method of antagonising one or more of the actions of thromboxane A₂ in a warm-blooded animal requiring such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim
 1. 11. N-Methanesulphonyl-4(Z)-6-([2,4,5-cis]-2-[1-methyl-1-phenoxyethyl]-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenamide, or a salt thereof. 